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Originally published In Press as doi:10.1074/jbc.M106981200 on August 29, 2001

J. Biol. Chem., Vol. 276, Issue 46, 43145-43151, November 16, 2001
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Design and Characterization of a Highly Selective Peptide Inhibitor of the Small Conductance Calcium-activated K+ Channel, SkCa2*

Vikram G. ShakkottaiDagger §, Imed Regaya§||, Heike WulffDagger , Ziad Fajloun||, Hiroaki TomitaDagger , Mohamed Fathallah||**, Michael D. CahalanDagger , J. Jay GargusDagger , Jean-Marc Sabatier||, and K. George ChandyDagger

From the Dagger  Department of Physiology and Biophysics, University of California, Irvine, California 92697, || CNRS Unité Mixte de Recherche 6560, Faculté de Médecine Nord 13014, Marseille, France, and ** CIC 9502, Assistance Publique des Hôpitaux de Marseille-INSERM, Hôpital Sainte Marguerite, Marseille 13009, France

Apamin-sensitive small conductance calcium-activated potassium channels (SKCa1-3) mediate the slow afterhyperpolarization in neurons, but the molecular identity of the channel has not been defined because of the lack of specific inhibitors. Here we describe the structure-based design of a selective inhibitor of SKCa2. Leiurotoxin I (Lei) and PO5, peptide toxins that share the RXCQ motif, potently blocked human SKCa2 and SKCa3 but not SKCa1, whereas maurotoxin, Pi1, Tskappa , and PO1 were ineffective. Lei blocked these channels more potently than PO5 because of the presence of Ala1, Phe2, and Met7. By replacing Met7 in the RXCQ motif of Lei with the shorter, unnatural, positively charged diaminobutanoic acid (Dab), we generated Lei-Dab7, a selective SKCa2 inhibitor (Kd = 3.8 nM) that interacts with residues in the external vestibule of the channel. SKCa3 was rendered sensitive to Lei-Dab7 by replacing His521 with the corresponding SKCa2 residue (Asn367). Intracerebroventricular injection of Lei-Dab7 into mice resulted in no gross central nervous system toxicity at concentrations that specifically blocked SKCa2 homotetramers. Lei-Dab7 will be a useful tool to investigate the functional role of SKCa2 in mammalian tissues.

* This study was supported by Grant MH59222 from the National Institutes of Health (to K. G. C.), by an American Heart Association Fellowship (to H. W.), and by CNRS and Cellpep S.A. (Paris, France) funds.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These two authors contributed equally to this work and should be considered co-first authors.

To whom correspondence should be addressed: Rm. 291, Joan Irvine Smith Hall, Medical School, University of California, Irvine, CA 92697. Tel.: 949-824-2133; Fax: 949-824-3143; E-mail: vshakkot@uci.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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